Main Outcomes Measures The primary outcome was coronary heart disease (CHD) (nonfatal myocardial
infarction and CHD death), with invasive breast cancer as the primary adverse
outcome. A global index summarizing the balance of risks and benefits included
the 2 primary outcomes plus stroke, pulmonary embolism (PE), endometrial cancer,
colorectal cancer, hip fracture, and death due to other causes.

Results On May 31, 2002, after a mean of 5.2 years of follow-up, the data and
safety monitoring board recommended stopping the trial of estrogen plus progestin
vs placebo because the test statistic for invasive breast cancer exceeded
the stopping boundary for this adverse effect and the global index statistic
supported risks exceeding benefits. This report includes data on the major
clinical outcomes through April 30, 2002. Estimated hazard ratios (HRs) (nominal
95% confidence intervals [CIs]) were as follows: CHD, 1.29 (1.02-1.63) with
286 cases; breast cancer, 1.26 (1.00-1.59) with 290 cases; stroke, 1.41 (1.07-1.85)
with 212 cases; PE, 2.13 (1.39-3.25) with 101 cases; colorectal cancer, 0.63
(0.43-0.92) with 112 cases; endometrial cancer, 0.83 (0.47-1.47) with 47 cases;
hip fracture, 0.66 (0.45-0.98) with 106 cases; and death due to other causes,
0.92 (0.74-1.14) with 331 cases. Corresponding HRs (nominal 95% CIs) for composite
outcomes were 1.22 (1.09-1.36) for total cardiovascular disease (arterial
and venous disease), 1.03 (0.90-1.17) for total cancer, 0.76 (0.69-0.85) for
combined fractures, 0.98 (0.82-1.18) for total mortality, and 1.15 (1.03-1.28)
for the global index. Absolute excess risks per 10 000 person-years attributable
to estrogen plus progestin were 7 more CHD events, 8 more strokes, 8 more
PEs, and 8 more invasive breast cancers, while absolute risk reductions per
10 000 person-years were 6 fewer colorectal cancers and 5 fewer hip fractures.
The absolute excess risk of events included in the global index was 19 per
10 000 person-years.

Conclusions Overall health risks exceeded benefits from use of combined estrogen
plus progestin for an average 5.2-year follow-up among healthy postmenopausal
US women. All-cause mortality was not affected during the trial. The risk-benefit
profile found in this trial is not consistent with the requirements for a
viable intervention for primary prevention of chronic diseases, and the results
indicate that this regimen should not be initiated or continued for primary
prevention of CHD.

Figures in this Article

The Women's Health Initiative (WHI) focuses on defining the risks and
benefits of strategies that could potentially reduce the incidence of heart
disease, breast and colorectal cancer, and fractures in postmenopausal women.
Between 1993 and 1998, the WHI enrolled 161 809 postmenopausal women
in the age range of 50 to 79 years into a set of clinical trials (trials of
low-fat dietary pattern, calcium and vitamin D supplementation, and 2 trials
of postmenopausal hormone use) and an observational study at 40 clinical centers
in the United States.1 This article reports
principal results for the trial of combined estrogen and progestin in women
with a uterus. The trial was stopped early based on health risks that exceeded
health benefits over an average follow-up of 5.2 years. A parallel trial of
estrogen alone in women who have had a hysterectomy is being continued, and
the planned end of this trial is March 2005, by which time the average follow-up
will be about 8.5 years.

The WHI clinical trials were designed in 1991-1992 using the accumulated
evidence at that time. The primary outcome for the trial of estrogen plus
progestin was designated as coronary heart disease (CHD). Potential cardioprotection
was based on generally supportive data on lipid levels in intermediate outcome
clinical trials, trials in nonhuman primates, and a large body of observational
studies suggesting a 40% to 50% reduction in risk among users of either estrogen
alone or, less frequently, combined estrogen and progestin.2- 5
Hip fracture was designated as a secondary outcome, supported by observational
data as well as clinical trials showing benefit for bone mineral density.6,7 Invasive breast cancer was designated
as a primary adverse outcome based on observational data.3,8
Additional clinical outcomes chosen as secondary outcomes that may plausibly
be affected by hormone therapy include other cardiovascular diseases; endometrial,
colorectal, and other cancers; and other fractures.3,6,9

The effect of hormones on overall health was an important consideration
in the design and conduct of the WHI clinical trial. In an attempt to summarize
important aspects of health benefits vs risks, a global index was defined
as the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary
embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death
due to other causes. Compared with total mortality, which may be too insensitive,
this index assigns additional weight to the 7 listed diseases. Procedures
for monitoring the trial involved semiannual comparisons of the estrogen plus
progestin and placebo groups with respect to each of the elements of the global
index and to the overall global index.

This report pertains primarily to estrogen plus progestin use among
healthy postmenopausal women, since only 7.7% of participating women reported
having had prior cardiovascular disease. During the course of the WHI trial,
the Heart and Estrogen/progestin Replacement Study (HERS) reported its principal
results.10 HERS was another blinded, randomized
controlled trial comparing the same regimen of estrogen plus progestin with
placebo among women with a uterus; however, in HERS, all 2763 participating
women had documented CHD prior to randomization. The HERS findings of no overall
effect on CHD but an apparent increased risk in the first year after randomization
seemed surprising given preceding observational studies of hormone use in
women with CHD.3 Subsequent to HERS, some investigators
reanalyzed their observational study data and were able to detect an early
elevation in CHD risk among women with prior CHD11- 13
but not in ostensibly healthy women,14 prompting
speculation that any early adverse effect of hormones on CHD incidence was
confined to women who have experienced prior CHD events.

The WHI is the first randomized trial to directly address whether estrogen
plus progestin has a favorable or unfavorable effect on CHD incidence and
on overall risks and benefits in predominantly healthy women.

METHODS

Study Population

Detailed eligibility criteria and recruitment methods have been published.1 Briefly, most women were recruited by population-based
direct mailing campaigns to age-eligible women, in conjunction with media
awareness programs. Eligibility was defined as age 50 to 79 years at initial
screening, postmenopausal, likelihood of residence in the area for 3 years,
and provision of written informed consent. A woman was considered postmenopausal
if she had experienced no vaginal bleeding for 6 months (12 months for 50-
to 54-year-olds), had had a hysterectomy, or had ever used postmenopausal
hormones. Major exclusions were related to competing risks (any medical condition
likely to be associated with a predicted survival of <3 years), safety
(eg, prior breast cancer, other prior cancer within the last 10 years except
nonmelanoma skin cancer, low hematocrit or platelet counts), and adherence
and retention concerns (eg, alcoholism, dementia).

A 3-month washout period was required before baseline evaluation of
women using postmenopausal hormones at initial screening. Women with an intact
uterus at initial screening were eligible for the trial of combined postmenopausal
hormones, while women with a prior hysterectomy were eligible for the trial
of unopposed estrogen. This report is limited to the 16 608 women with
an intact uterus at baseline who were enrolled in the trial component of estrogen
plus progestin vs placebo. The protocol and consent forms were approved by
the institutional review boards for all participating institutions (see Acknowledgment).

Study Regimens, Randomization, and Blinding

Combined estrogen and progestin was provided in 1 daily tablet containing
conjugated equine estrogen (CEE), 0.625 mg, and medroxyprogesterone acetate
(MPA), 2.5 mg (Prempro, Wyeth Ayerst, Philadelphia, Pa). A matching placebo
was provided to the control group. Eligible women were randomly assigned to
receive estrogen plus progestin or placebo after eligibility was established
and baseline assessments made (Figure 1).
The randomization procedure was developed at the WHI Clinical Coordinating
Center and implemented locally through a distributed study database, using
a randomized permuted block algorithm, stratified by clinical center site
and age group. All study medication bottles had a unique bottle number and
bar code to allow for blinded dispensing.

Initially, the design allowed women with a uterus to be randomized to
receive unopposed estrogen, estrogen plus progestin, or placebo. After the
release of the Postmenopausal Estrogen/Progestin Intervention (PEPI) trial
results15 indicating that long-term adherence
to unopposed estrogen was not feasible in women with a uterus, the WHI protocol
was changed to randomize women with a uterus to only estrogen plus progestin
or placebo in equal proportions. The 331 women previously randomized to unopposed
estrogen were unblinded and reassigned to estrogen plus progestin. These women
are included in the estrogen plus progestin group in this report, resulting
in 8506 participants in the estrogen plus progestin group vs 8102 in the placebo
group. Analysis of the data excluding the women randomized before this protocol
change did not affect the results. Considerable effort was made to maintain
blinding of other participants and clinic staff. When required for safety
or symptom management, an unblinding officer provided the clinic gynecologist,
who was not involved with study outcomes activities, with the treatment assignment.

Follow-up

Study participants were contacted by telephone 6 weeks after randomization
to assess symptoms and reinforce adherence. Follow-up for clinical events
occurred every 6 months, with annual in-clinic visits required. At each semiannual
contact, a standardized interview collected information on designated symptoms
and safety concerns, and initial reports of outcome events were obtained using
a self-administered questionnaire. Adherence to study interventions was assessed
by weighing of returned bottles. The study protocol required annual mammograms
and clinical breast examinations; study medications were withheld if safety
procedures were not performed, but these participants continued to be followed
up. Electrocardiograms were collected at baseline and at follow-up years 3
and 6.

Data Collection, Management, and Quality Assurance

All data were collected on standardized study forms by certified staff
according to documented study procedures. Study data were entered into a local
clinical center database developed and maintained by the Clinical Coordinating
Center and provided to each site in the form of a local area network connected
to the Clinical Coordinating Center through a wide area network. Data quality
was ensured through standard data entry mechanisms, routine reporting and
database checks, random chart audits, and routine site visits.

Maintenance/Discontinuation of Study Medications

During the trial, some flexibility of the dosages of both estrogen and
progestin was allowed to manage symptoms such as breast tenderness and vaginal
bleeding. Vaginal bleeding was managed according to an algorithm that accounted
for the time since randomization, severity of the bleeding, treatment assignment,
and endometrial histology. Women who had a hysterectomy after randomization
for indications other than cancer were switched to unopposed estrogen or the
corresponding placebo without unblinding. These women are included in the
original randomization group for analyses.

Permanent discontinuation of study medication was required by protocol
for women who developed breast cancer, endometrial pathologic state (hyperplasia
not responsive to treatment, atypia, or cancer), deep vein thrombosis (DVT)
or PE, malignant melanoma, meningioma, triglyceride level greater than 1000
mg/dL (11.3 mmol/L), or prescription of estrogen, testosterone, or selective
estrogen-receptor modulators by their personal physician. Medications were
temporarily discontinued in participants who had acute myocardial infarction
(MI), stroke, fracture, or major injury involving hospitalization, surgery
involving use of anesthesia, any illness resulting in immobilization for more
than 1 week, or any other severe illness in which hormone use is temporarily
inappropriate.

Outcome Ascertainment

Cardiovascular Disease Coronary heart disease was defined as acute MI requiring overnight hospitalization,
silent MI determined from serial electrocardiograms (ECGs), or CHD death.
The diagnosis of acute MI was established according to an algorithm adapted
from standardized criteria16 that included
cardiac pain, cardiac enzyme and troponin levels, and ECG readings. The primary
analyses included both definite and probable MIs as defined by the algorithm.
Myocardial infarction occurring during surgery and aborted MIs were included.
An aborted MI was defined as chest pain and ECG evidence of acute MI at presentation,
an intervention (eg, thrombolysis) followed by resolution of ECG changes,
and all cardiac enzyme levels within normal ranges. Silent MI was diagnosed
by comparing baseline and follow-up ECGs at 3 and 6 years after randomization.
Coronary death was defined as death consistent with CHD as underlying cause
plus 1 or more of the following: preterminal hospitalization with MI within
28 days of death, previous angina or MI and no potentially lethal noncoronary
disease, death resulting from a procedure related to coronary artery disease,
or death certificate consistent with CHD as the underlying cause. Stroke diagnosis
was based on rapid onset of a neurologic deficit lasting more than 24 hours,
supported by imaging studies when available. Pulmonary embolism and DVT required
clinical symptoms supported by relevant diagnostic studies.

Cancer Breast, colorectal, endometrial, and other cancers were confirmed by
pathological reports when available. Current data indicate that at least 98%
of breast, colorectal, and endometrial cancers and 92% of other cancers were
documented with pathological reports.

Fractures Reports of hip, vertebral, and other osteoporotic fractures (including
all fractures except those of the ribs, chest/sternum, skull/face, fingers,
toes, and cervical vertebrae) were routinely ascertained. All fracture outcomes
were verified by radiology reports. Study radiographs were not obtained to
ascertain subclinical vertebral fractures.

This report is based on outcomes adjudicated by clinical center physician
adjudicators, as used for trial-monitoring purposes. Clinical center physician
adjudicators were centrally trained and blinded to treatment assignment and
participants' symptoms. Future communications will report results based on
centrally adjudicated outcomes and will include a broader range of outcomes
with more extensive explanatory analyses. Since this report is presented before
the planned study closeout, outcome information is still being collected and
adjudicated. Local adjudication is complete for approximately 96% of the designated
self-reported events. To date, agreement rates between local and central adjudication
are: MI, 84%; revascularization procedures, 97%; PE, 89%; DVT, 84%; stroke,
94%; invasive breast cancer, 98%; endometrial cancer, 96%; colorectal cancer,
98%; hip fracture, 95%; and specific cause of death, 82%. When related cardiovascular
conditions are combined (eg, when unstable angina or congestive heart failure
is grouped with MI), agreement rates exceed 94% for cardiovascular disease
and 90% for specific cause of death.

Statistical Analyses

All primary analyses use time-to-event methods and are based on the
intention-to-treat principle. For a given outcome, the time of event was defined
as the number of days from randomization to the first postrandomization diagnosis,
as determined by the local adjudicator. For silent MIs, the date of the follow-up
ECG applied. Participants without a diagnosis were censored for that event
at the time of last follow-up contact. Primary outcome comparisons are presented
as hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox proportional
hazards analyses,17 stratified by clinical
center, age, prior disease, and randomization status in the low-fat diet trial.

Two forms of CIs are presented, nominal and adjusted. Nominal 95% CIs
describe the variability in the estimates that would arise from a simple trial
for a single outcome. Although traditional, these CIs do not account for the
multiple statistical testing issues (across time and across outcome categories)
that occurred in this trial, so the probability is greater than .05 that at
least 1 of these CIs will exclude unity under an overall null hypothesis.
The adjusted 95% CIs presented herein use group sequential methods to correct
for multiple analyses over time. A Bonferroni correction for 7 outcomes as
specified in the monitoring plan (described herein) was applied to all clinical
outcomes other than CHD and breast cancer, the designated primary and primary
adverse effect outcomes, and the global index. The adjusted CIs are closely
related to the monitoring procedures and, as such, represent a conservative
assessment of the evidence. This report focuses primarily on results using
the unadjusted statistics and also relies on consistency across diagnostic
categories, supportive data from other studies, and biologic plausibility
for interpretation of the findings.

Data and Safety Monitoring

Trial monitoring guidelines for early stopping considerations were based
on O'Brien-Fleming boundaries18 using asymmetric
upper and lower boundaries: a 1-sided, .025-level upper boundary for benefit
and 1-sided, .05-level lower boundaries for adverse effects. The adverse-effect
boundaries were further adjusted with a Bonferroni correction for the 7 major
outcomes other than breast cancer that were specifically monitored (CHD, stroke,
PE, colorectal cancer, endometrial cancer, hip fracture, and death due to
other causes). The global index of monitored outcomes played a supportive
role as a summary measure of the overall balance of risks and benefits. Trial
monitoring for early stopping considerations was conducted semiannually by
an independent data and safety monitoring board (DSMB). Aspects of the monitoring
plan have been published.19

RESULTS

Trial Monitoring and Early Stopping Formal monitoring began in the fall of 1997 with the expectation of
final analysis in 2005 after an average of approximately 8.5 years of follow-up.
Late in 1999, with 5 interim analyses completed, the DSMB observed small but
consistent early adverse effects in cardiovascular outcomes and in the global
index. None of the disease-specific boundaries had been crossed. In the spring
of 2000 and again in the spring of 2001, at the direction of the DSMB, hormone
trial participants were given information indicating that increases in MI,
stroke, and PE/DVT had been observed and that the trial continued because
the balance of risks and benefits remained uncertain.

In reviewing the data for the 10th interim analyses on May 31, 2002,
the DSMB found that the adverse effects in cardiovascular diseases persisted,
although these results were still within the monitoring boundaries. However,
the design-specified weighted log-rank test statistic for breast cancer (z = −3.19) crossed the designated boundary (z = −2.32) and the global index was supportive of
a finding of overall harm (z = −1.62). Updated
analyses including 2 months of additional data, available by the time of the
meeting, did not appreciably change the overall results. On the basis of these
data, the DSMB concluded that the evidence for breast cancer harm, along with
evidence for some increase in CHD, stroke, and PE, outweighed the evidence
of benefit for fractures and possible benefit for colon cancer over the average
5.2-year follow-up period. Therefore, the DSMB recommended early stopping
of the estrogen plus progestin component of the trial. Because the balance
of risks and benefits in the unopposed-estrogen component remains uncertain,
the DSMB recommended continuation of that component of the WHI. Individual
trial participants have been informed.

Baseline Characteristics

There were no substantive differences between study groups at baseline;
8506 women were randomized into the estrogen plus progestin group and 8102
into the placebo group (Table 1a).
The mean (SD) age was 63.3 (7.1) years. Two thirds of the women who reported
prior or current hormone use had taken combined hormones and one third had
used unopposed estrogen.

Prevalence of prior cardiovascular disease was low and levels of cardiovascular
risk factors were consistent with a generally healthy population of postmenopausal
women. An assessment of commonly studied breast cancer risk factors, both
individually and combined using the Gail model,20
indicate that the cohort in general was not at increased risk of breast cancer.

Follow-up, Adherence, and Unblinding

Vital status is known for 16 025 randomized participants (96.5%),
including 449 (2.7%) known to be deceased. A total of 583 (3.5%) participants
were lost to follow-up or stopped providing outcomes information for more
than 18 months. The remaining 15 576 (93.8%) provided recent outcome
information (Figure 1).

At the time of this report, all women had been enrolled for at least
3.5 years, with an average follow-up of 5.2 years and a maximum of 8.5 years.
A substantial number of women had stopped taking study drugs at some time
(42% of estrogen plus progestin and 38% of placebo). Dropout rates over time
(Figure 2) exceeded design projections,
particularly early on, but compare favorably with community-based adherence
to postmenopausal hormones.21 Some women in
both groups initiated hormone use through their own clinician (6.2% in the
estrogen plus progestin group and 10.7% in the placebo group cumulatively
by the sixth year). These "drop-in" rates were also greater than expected.

Dropout refers to women who discontinued study medication; drop-in,
women who discontinued study medication and received postmenopausal hormones
through their own clinician.

At the time of this report, clinic gynecologists had been unblinded
to treatment assignment for 3444 women in the estrogen plus progestin group
and 548 women in the placebo group, primarily to manage persistent vaginal
bleeding. During the trial, 248 women in the estrogen plus progestin group
and 183 in the placebo group had a hysterectomy.

Clinical Outcomes

Cardiovascular Disease Overall CHD rates were low (Table
2). The rate of women experiencing CHD events was increased by 29%
for women taking estrogen plus progestin relative to placebo (37 vs 30 per
10 000 person-years), reaching nominal statistical significance (at the
.05 level). Most of the excess was in nonfatal MI. No significant differences
were observed in CHD deaths or revascularization procedures (coronary artery
bypass grafting or percutaneous transluminal coronary angioplasty). Stroke
rates were also higher in women receiving estrogen plus progestin (41% increase;
29 vs 21 per 10 000 person-years), with most of the elevation occurring
in nonfatal events. Women in the estrogen plus progestin group had 2-fold
greater rates of venous thromboembolism (VTE), as well as DVT and PE individually,
with almost all associated CIs excluding 1. Rates of VTE were 34 and 16 per
10 000 person-years in the estrogen plus progestin and placebo groups,
respectively. Total cardiovascular disease, including other events requiring
hospitalization, was increased by 22% in the estrogen plus progestin group.

Fractures This cohort experienced low hip fracture rates (10 per 10 000 person-years
in the estrogen plus progestin group vs 15 per 10 000 person-years in
the placebo group). Estrogen plus progestin reduced the observed hip and clinical
vertebral fracture rates by one third compared with placebo, both nominally
significantly. The reductions in other osteoporotic fractures (23%) and total
fractures (24%) were statistically significant (all associated CIs exclude
1).

The global index showed a nominally significant 15% increase in the
estrogen plus progestin group (170 vs 151 per 10 000 person-years). There
were no differences in mortality or cause of death between groups (Table 3).

Time Trends

The Kaplan Meier estimates of cumulative hazards (Figure 3) for CHD indicate that the difference between treatment
groups began to develop soon after randomization. These curves provide little
evidence of convergence through 6 years of follow-up. The cumulative hazards
for stroke begin to diverge between 1 and 2 years after randomization, and
this difference persists beyond the fifth year. For PE, the curves separate
soon after randomization and show continuing adverse effects throughout the
observation period. For breast cancer, the cumulative hazard functions are
comparable through the first 4 years, at which point the curve for estrogen
plus progestin begins to rise more rapidly than that for placebo. Curves for
colorectal cancer show benefit beginning at 3 years, and curves for hip fracture
show increasing cumulative benefit over time. The difference in hazard rates
for the global index (Figure 4)
suggests a gradual increase in adverse effects compared with benefits for
estrogen plus progestin through year 5, with a possible narrowing of the difference
by year 6; however, HR estimates tend to be unstable beyond 6 years after
randomization. Total mortality rates are indistinguishable between estrogen
plus progestin and placebo.

Figure 4. Kaplan-Meier Estimates of Cumulative
Hazards for Global Index and Death

Tests for linear trends with time since randomization, based on a Cox
proportional hazards model with a time-dependent covariate, detected no trend
with time for CHD, stroke, colorectal cancer, hip fracture, total mortality,
or the global index (Table 4).
There was some evidence for an increasing risk of breast cancer over time
with estrogen plus progestin (z = 2.56 compared with
a nominal z score for statistical significance of
1.96) and a decreasing risk of VTE with time (z = −2.45).
These results must be viewed cautiously because the number of events in each
interval is modest, the data in later years are still incomplete, and later
year comparisons are limited to women still at risk of their first event for
that outcome.

Subgroup Analyses

Cardiovascular Disease A small subset of women (n = 400; average follow-up, 57.4 months) in
WHI reported conditions at baseline that would have made them eligible for
HERS, ie, prior MI or revascularization procedures. Among these women with
established coronary disease, the HR for subsequent CHD for estrogen plus
progestin relative to placebo was 1.28 (95% CI, 0.64-2.56) with 19 vs 16 events.
The remaining women, those without prior CHD, had an identical HR for CHD
(145 vs 106; HR, 1.28; 95% CI, 1.00-1.65). Few women with a history of VTE
were enrolled, but these data suggest a possibility that these women may be
at greater risk of future VTE events when taking estrogen plus progestin (7
vs 1; HR, 4.90; 95% CI, 0.58-41.06) than those without a history of VTE (144
vs 66; HR, 2.06; 95% CI, 1.54-2.76). For stroke, prior history did not confer
additional risk (1 vs 5 in women with prior stroke; HR, 0.46; 95% CI, 0.05-4.51;
126 vs 80 with no prior stroke; HR, 1.47; 95% CI, 1.11-1.95). No noteworthy
interactions with age, race/ethnicity, body mass index, prior hormone use,
smoking status, blood pressure, diabetes, aspirin use, or statin use were
found for the effect of estrogen plus progestin on CHD, stroke, or VTE.

Further Analyses

Because a number of women stopped study medications during follow-up,
several analyses were performed to examine the sensitivity of the principal
HR estimates to actual use of study medications. Analyses that censored a
woman's event history 6 months after becoming nonadherent (using <80% of
or stopping study drugs) produced the largest changes to estimated effect
sizes. This approach increased HRs to 1.51 for CHD, to 1.49 for breast cancer,
to 1.67 for stroke, and to 3.29 for VTE. Analyses attributing events to actual
hormone use ("as treated," allowing for a 6-month lag) produced more modest
changes to these estimates. Analyses excluding women randomized during the
period when the unopposed-estrogen component was open to women with a uterus
and analyses stratifying by enrollment period did not substantially affect
the results. These analyses suggest that the intention-to-treat estimates
of HRs may somewhat underestimate the effect sizes relative to what would
be observed with full adherence to study medications.

COMMENT

The WHI provides evidence from a large randomized trial that addresses
the important issue of whether most women with an intact uterus in the decades
of life following menopause should consider hormone therapy to prevent chronic
disease. The WHI enrolled a cohort of mostly healthy, ethnically diverse women,
spanning a large age range (50-79 years at baseline). It is noteworthy that
the increased risks for cardiovascular disease and invasive breast cancer
were present across racial/ethnic and age strata and were not influenced by
the antecedent risk status or prior disease. Hence, the results are likely
to be generally applicable to healthy women in this age range. At the time
the trial was stopped, the increases in numbers of invasive breast cancers,
CHD, stroke, and PE made approximately equal contributions to harm in the
estrogen plus progestin group compared with placebo, which were not counterbalanced
by the smaller reductions in numbers of hip fractures and colorectal cancers.

Cardiovascular Disease

Even though the trial was stopped early for harm from breast cancer,
a sufficient number of CHD events had occurred by 5.2 years of average follow-up
to suggest that continuation to the planned end would have been unlikely to
yield a favorable result for the primary outcome of CHD. Even if there were
a reversal of direction toward benefit of a magnitude seen in the observational
studies (ie, a risk reduction of 55%) during the remaining years, conditional
power analyses indicate that less than 10% power remained for showing potential
benefit if the trial continued.

The WHI finding that estrogen plus progestin does not confer benefit
for preventing CHD among women with a uterus concurs with HERS findings among
women with clinically apparent CHD,10 with
the Estrogen Replacement for Atherosclerosis trial, in which estrogen plus
progestin did not inhibit progression,23 and
with a trial in women with unstable angina that did not observe a reduction
in ischemic events.24 The finding of an increased
risk after initiation of treatment in WHI is similar to HERS. In HERS, after
4.1 and 6.8 years of follow-up, hormone therapy did not increase or decrease
risk of cardiovascular events in women with CHD.25
The WHI extends these findings to include a wider range of women, including
younger women and those without clinically apparent CHD, and indicates that
the risk may persist for some years.

Unlike CHD, the excess risk of stroke in the estrogen plus progestin
group was not present in the first year but appeared during the second year
and persisted through the fifth year. Preliminary analyses indicate that the
modest difference in blood pressure between groups does not contribute much
to an explanation of the increase in strokes (data not shown). The findings
in WHI for stroke are consistent with but somewhat more extreme than those
of HERS, which reported a nonsignificant 23% increase in the treatment group.26 The results were also more extreme than those of
the Women's Estrogen and Stroke Trial of estradiol (without progestin) in
women with prior stroke, which found no effect of estrogen on recurrent strokes
overall but some increase in the first 6 months.27
Trials of the effect of estradiol on carotid intima-media thickness have yielded
conflicting results.28,29 At least
1 observational study has suggested that that use of estrogen plus progestin
is associated with higher risk of stroke than estrogen alone.14
In WHI, there was no indication that excess strokes due to estrogen plus progestin
were more likely to occur in older women, in women with prior stroke history,
by race/ethnicity, or in women with high blood pressure at baseline. Therefore,
it appears that estrogen plus progestin increases the risk of strokes in apparently
healthy women.

Venous thromboembolism is an expected complication of postmenopausal
hormones, and the pattern over time in WHI is consistent with the findings
from HERS and several observational studies.30,31

Cancer

The WHI is the first randomized controlled trial to confirm that combined
estrogen plus progestin does increase the risk of incident breast cancer and
to quantify the degree of risk. The WHI could not address the risk of death
due to breast cancer because with the relatively short follow-up time, few
women in the WHI have thus far died as a result of breast cancer (3 in the
active treatment group and 2 in the placebo group). The risk of breast cancer
emerged several years after randomization. After an average follow-up of about
5 years, the adverse effect on breast cancer had crossed the monitoring boundary.
The 26% excess of breast cancer is consistent with estimates from pooled epidemiological
data, which reported a 15% increase for estrogen plus progestin use for less
than 5 years and a 53% increase for use for more than 5 years.32
It is also consistent with the (nonsignificant) 27% increase found after 6.8
years of follow-up in HERS.33

With more common use of estrogen plus progestin, several epidemiological
studies have reported that estrogen plus progestin appears to be associated
with greater risk of breast cancer than estrogen alone.34- 37
In the PEPI trial, women in the 3 estrogen plus progestin groups had much
greater increases in mammographic density (a predictor of breast cancer) than
women in the estrogen or placebo groups.38
In WHI, the HR for estrogen plus progestin was not higher in women with a
family history or other risk factors for breast cancer, except for reported
prior use of postmenopausal hormones. This may suggest a cumulative effect
of years of exposure to postmenopausal hormones.

Endometrial cancer rates were low and were not increased by 5 years
of estrogen plus progestin exposure. Close monitoring for bleeding and treatment
of hyperplasia may contribute to the absence of increased risk of endometrial
cancer.

The reduction in colorectal cancer in the hormone group is consistent
with observational studies, which have suggested fairly consistently that
users of postmenopausal hormones may be at lower risk of colorectal cancer.39 The mechanisms by which hormone use might reduce
risk are unclear. Results from other trials of postmenopausal hormones will
help resolve the effects of hormones on colorectal cancer.40

Fractures

The reductions in clinical vertebral fractures, other osteoporotic fractures,
and combined fractures supported the benefit for hip fractures found in this
trial. These findings are consistent with the observational data and limited
data from clinical trials41 and are also consistent
with the known ability of estrogen (with or without progestin) to maintain
bone mineral density.42 The WHI is the first
trial with definitive data supporting the ability of postmenopausal hormones
to prevent fractures at the hip, vertebrae, and other sites.

Overall Risks and Benefits

At the end of the trial, the global index indicated that there were
more harmful than beneficial outcomes in the estrogen plus progestin group
vs the placebo group. The monitored outcomes included in the global index
were selected to represent diseases of serious import that estrogen plus progestin
treatment might affect, and do not include a variety of other conditions and
measures that may be affected in unfavorable or favorable ways (eg, gallbladder
disease, diabetes, quality of life, and cognitive function). The data on these
and other outcomes will be the subject of future publications. All-cause mortality
was balanced between the groups; however, longer follow-up may be needed to
assess the impact of the incident diseases on total mortality.

During the 5.2 years of this trial, the number of women experiencing
a global index event was about 100 more per 10 000 women taking estrogen
plus progestin than taking placebo. If the current findings can be extrapolated
to an even longer treatment duration, the absolute risks and benefits associated
with estrogen plus progestin for each of these conditions could be substantial
and on a population basis could account for tens of thousands of conditions
caused, or prevented, by hormone use.

Limitations

This trial tested only 1 drug regimen, CEE, 0.625 mg/d, plus MPA, 2.5
mg/d, in postmenopausal women with an intact uterus. The results do not necessarily
apply to lower dosages of these drugs, to other formulations of oral estrogens
and progestins, or to estrogens and progestins administered through the transdermal
route. It remains possible that transdermal estradiol with progesterone, which
more closely mimics the normal physiology and metabolism of endogenous sex
hormones, may provide a different risk-benefit profile. The WHI findings for
CHD and VTE are supported by findings from HERS, but there is no other evidence
from clinical trials for breast cancer and colorectal cancer, and only limited
data from trials concerning fractures.

Importantly, this trial could not distinguish the effects of estrogen
from those of progestin. The effects of progestin may be important for breast
cancer and atherosclerotic diseases, including CHD and stroke. Per protocol,
in a separate and adequately powered trial, WHI is testing the hypothesis
of whether oral estrogen will prevent CHD in 10 739 women who have had
a hysterectomy. The monitoring of this trial is similar to that for the trial
of estrogen plus progestin. At an average follow-up of 5.2 years, the DSMB
has recommended that this trial continue because the balance of overall risks
and benefits remains uncertain. These results are expected to be available
in 2005, at the planned termination.

The relatively high rates of discontinuation in the active treatment
arm (42%) and crossover to active treatment in the placebo arm (10.7%) are
a limitation of the study; however, the lack of adherence would tend to decrease
the observed treatment effects. Thus, the results presented here may underestimate
the magnitude of both adverse effects on cardiovascular disease and breast
cancer and the beneficial effects on fractures and colorectal cancer among
women who adhere to treatment.

The fact that the trial was stopped early decreases the precision of
estimates of long-term treatment effects. A longer intervention period might
have shown more pronounced benefit for fractures and might have yielded a
more precise test of the hypothesis that treatment reduces colorectal cancer.
Nonetheless, it appears unlikely that benefit for CHD would have emerged by
continuing the trial to its planned termination. The trial results indicate
that treatment for up to 5.2 years is not beneficial overall and that there
is early harm for CHD, continuing harm for stroke and VTE, and increasing
harm for breast cancer with increasing duration of treatment. This risk-benefit
profile is not consistent with the requirements for a viable intervention
for the primary prevention of chronic diseases.

Implications

The WHI trial results provide the first definitive data on which to
base treatment recommendations for healthy postmenopausal women with an intact
uterus. This trial did not address the short-term risks and benefits of hormones
given for the treatment of menopausal symptoms. On the basis of HERS and other
secondary prevention trials, the American Heart Association recommended against
initiating postmenopausal hormones for the secondary prevention of cardiovascular
disease.43 The American Heart Association made
no firm recommendation for primary prevention while awaiting the results from
randomized clinical trials such as WHI, and stated that continuation of the
treatment should be considered on the basis of established noncoronary benefits
and risks, possible coronary benefits and risks, and patient preference.

Results from WHI indicate that the combined postmenopausal hormones
CEE, 0.625 mg/d, plus MPA, 2.5 mg/d, should not be initiated or continued
for the primary prevention of CHD. In addition, the substantial risks for
cardiovascular disease and breast cancer must be weighed against the benefit
for fracture in selecting from the available agents to prevent osteoporosis.

The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in
postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions
(PEPI) Trial. JAMA.1996;275:370-375.

The Writing Group for the PEPI Trial. Effects of hormone replacement therapy on endometrial histology in
postmenopausal women: the Postmenopausal Estrogen/Progestin Interventions
(PEPI) Trial. JAMA.1996;275:370-375.

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